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Acute myeloid leukemia (AML) is a fatal hematologic disease. Diagnosis and proper treatment are important for prognosis. High myeloperoxidase (MPO) expression AML cells are characterized with high levels of hypochlorite (ClO - ). In this study, we report a ClO - -activated theranostic agent, FNC , for AML therapy. FNC responds to ClO - specifically in high MPO expression AML cells, resulting in bright fluorescence and chlorambucil release. FNC can be used to quickly distinguish high MPO expression AML cells from other cells, including low MPO expression leukemia and activated inflammatory cells. FNC exhibits selective toxicity to highly MPO expression AML cells and can efficiently inhibit tumor growth. Meanwhile, FNC can be used to indicate differentiation through the detection of ClO - .

High-entropy oxides (HEOs), featuring infinite chemical composition and exceptional physicochemical properties, are attracting much attention. The configurational entropy caused by a component disorder of HEOs is popularly believed to be the main driving force for thermal stability, while the role of vibrational entropy in the thermodynamic landscape has been neglected. In this study, we systematically investigated the vibrational entropy of multicomponent rutile oxides (including Fe 0.5 Ta 0.5 O 2 , Fe 0.333 Ti 0.333 Ta 0.333 O 2 , Fe 0.25 Ti 0.25 Ta 0.25 Sn 0.25 O 2 , and Fe 0.21 Ti 0.21 Ta 0.21 Sn 0.21 Ge 0.16 O 2 ) by precise heat capacity measurements. It is found that vibrational entropy gradually decreases with increasing component disorder, beyond what one could expect from an equilibrium thermodynamics perspective. Moreover, all multicomponent rutile oxides exhibit a positive excess vibrational entropy at 298.15 K. Upon examinations of configuration disorder, size mismatch, phase transition, and polyhedral distortions, we demonstrate that the excess vibrational entropy plays a pivotal role in lowering the crystallization temperature of multicomponent rutile oxides. These findings represent the first experimental confirmation of the role of lattice vibrations in the thermodynamic landscape of rutile HEOs. In particular, vibrational entropy could serve as a novel descriptor to guide the predictive design of multicomponent oxide materials.

Accurate identification of single nucleotide variants (SNVs) in key driver genes holds a significant value for disease diagnosis and treatment. Fluorescent probes exhibit tremendous potential in specific, high-resolution, and rapid detection of SNVs. However, additional steps are required in most post-PCR assays to convert double-stranded DNA (dsDNA) products into single-stranded DNA (ssDNA), enabling them to possess hybridization activity to trigger subsequent reactions. This process not only prolongs the complexity of the experiment but also introduces the risk of losing target information. In this study, we proposed two strategies for enriching active double-stranded DNA, involving PCR based on obstructive groups and cleavable units. Building upon this, we explored the impact of modified units on the strand displacement reaction (SDR) and assessed their discriminatory efficacy for mutations. The results showed that detection of low variant allele frequencies (VAF) as low as 0.1% can be achieved. The proposed strategy allowed orthogonal identification of 45 clinical colorectal cancer tissue samples with 100% specificity, and the results were generally consistent with sequencing results. Compared to existing methods for enriching active targets, our approach offers a more diverse set of enrichment strategies, characterized by the advantage of being simple and fast and preserving original information to the maximum extent. The objective of this study is to offer an effective solution for the swift and facile acquisition of active double-stranded DNA. We anticipate that our work will facilitate the practical applications of SDR based on dsDNA.

Per- and polyfluoroalkyl substances (PFAS) are extensively utilized in varieties of products and tend to accumulate in the human body including umbilical cord blood and embryos/fetuses. In this study, we conducted an assessment and comparison of the potential early developmental toxicity of perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid, perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate, and perfluorobutyric acid at noncytotoxic concentrations relevant to human exposure using models based on human embryonic stem cells in both three-dimensional embryoid body (EB) and monolayer differentiation configurations. All six compounds influenced the determination of cell fate by disrupting the expression of associated markers in both models and, in some instances, even led to alterations in the formation of cystic EBs. The expression of cilia-related gene IFT122 was significantly inhibited. Additionally, PFOS and PFOA inhibited ciliogenesis, while PFOA specifically reduced the cilia length. Transcriptome analysis revealed that PFOS altered 1054 genes and disrupted crucial signaling pathways such as WNT and TGF-β, which play integral roles in cilia transduction and are critical for early embryonic development. These results provide precise and comprehensive insights into the potential adverse health effects of these six PFAS compounds directly concerning early human embryonic development.

In recent years, rapid industrial development has resulted in the production and exposure of a substantial number of compounds to the human body. This has created an urgent need in environmental toxicology for models that are efficient, accurate, and cost-effective in evaluating the health impacts of these compounds on humans. Over the past seven decades, various cancer cell lines and immortalized cell lines have made significant contributions to the advancement of research on organ toxicity. Pluripotent stem cell technology, especially toxicological models derived from pluripotent stem cells, presents modern environmental toxicologists with high-throughput, species-relevant, and predictive options. In this comprehensive review, we assess the characteristics of representative human cancer cell lines and immortalized cell lines in environmental toxicology, as well as introduce two distinct human pluripotent stem cell types and their innovative toxicological models. We explore their applications and prospects in the field of environmental toxicology, while also addressing the readiness of in vitro models to confront the emerging challenges of the future., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, and American Chemical Society.)

Competing Interests: The authors declare no competing financial interest.

Bisphenol A (BPA) is a common endocrine disruptor widely used in the production of electronic, sports, and medical equipment, as well as consumer products like milk bottles, dental sealants, and thermal paper. Despite its widespread use, current assessments of BPA exposure risks remain limited due to the lack of comprehensive cross-species comparative analyses. To address this gap, we conducted a study aimed at identifying genes and fundamental molecular processes consistently affected by BPA in various species and tissues, employing an effective data integration method and bioinformatic analyses. Our findings revealed that exposure to BPA led to significant changes in processes like lipid metabolism, proliferation, and apoptosis in the tissues/cells of mammals, fish, and nematodes. These processes were found to be commonly affected in adipose, liver, mammary, uterus, testes, and ovary tissues. Additionally, through an in-depth analysis of signaling pathways influenced by BPA in different species and tissues, we observed that the JUN/FOS, EGFR, ER, PPARG, and P53 pathways, along with their downstream key transcription factors and kinases, were all impacted by BPA. Our study provides compelling evidence that BPA indeed induces similar toxic effects across different species and tissues. Furthermore, our investigation sheds light on the underlying molecular mechanisms responsible for these toxic effects. By uncovering these mechanisms, we gain valuable insights into the potential health implications associated with BPA exposure, highlighting the importance of comprehensive assessments and awareness of this widespread endocrine disruptor.

Near-infrared (NIR) quantum dot (QD) light-emitting diodes (LEDs) (NIR-QLEDs) for recognition and tracking applications underpin the future of night-vision technology. However, the performance of environmentally benign materials and devices has lagged far behind that of their Pb-containing counterparts. In this study, we demonstrate the superior performance of NIR-QLEDs based on efficient AgAuSe QDs with contact interface mediation. Consequently, we reveal that using cysteamine-treated QD film contact heterointerfaces can effectively eliminate contact defects in devices and preserve their excellent emissive properties. Additionally, the dipole moment orientation of the coordinated additives is inverse of the heterojunction potential difference, simultaneously blocking electrons and enhancing hole injection in operando, optimizing the LED charge injection balance. These devices exhibit a high external quantum efficiency (EQE) and a power conversion efficiency (PCE) of 15.8 and 12.7% at 1046 nm, respectively, a sub-band gap turn-on voltage of 0.9 V, and a low current density (over 10% of the EQE from 0.0017 to 0.31 mA cm -2 ). These are the highest EQE and PCE values ever reported for environmentally benign NIR-QLEDs. The results of this study can provide a general strategy for the practical application of QDs in electroluminescent devices.

This study aimed to explore the enhancive effects of butterfly pea flower (BF) extracts on metabolic and immune homeostasis in a low-grade inflammation mouse model. The BF extract was found to contain mainly anthocyanins among other flavonoids. BF supplementation alleviated metabolic endotoxemia by lowering the plasma glucose, lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α) levels and restored lipid metabolism and the balance between Treg and Th17 cells, thereby inhibiting the dysfunctional liver and abdominal white adipose tissues. BF extract increased the tight junction protein expression and reduced the expression of proinflammatory cytokines, therefore sustaining the colonic mucosa structure. Furthermore, BF extracts reshaped the gut microbiota structure characterized by significantly promoted SCFA-producing gut microbiota such as Akkermansia and Butyricicoccaceae . Additionally, BF extracts enhanced fecal primary bile acid (BA) levels and modulated bile acid signaling in the liver and ileum to facilitate BA synthesis for the restoration of lipid metabolism. In summary, anthocyanin-enriched BF extracts alleviated the profound negative dietary alterations and helped maintain the metabolic health by modulating the various aspects of the gut microenvironment and enhancing hepatic bile acid synthesis.

Regulating non-apoptotic cell death of cancer cells provides a promising strategy to overcome apoptosis resistance during cancer treatment. Lipids are essential components to exacerbate several non-apoptotic cell death pathways. In the present study, unsaturated fatty acid (UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic acid have the potential to affect lipid metabolism. Notably, UFA liposomes markedly increased cellular reactive oxygen species (ROS) and down-regulated the expression of glutathione peroxidase 4 (GPX4) in tumor cells, resulting in lipid peroxidation, which in turn caused rapid membrane rupture and induced non-apoptotic cell death of tumor cells. Concomitantly, UFA liposomes induced ROS-mediated tumor-associated macrophages toward a tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment. Consequently, UFA liposomes substantially inhibited tumor growth in a melanoma model by promoting lipid peroxidation, inducing non-apoptotic cell death of tumor cells, and increasing infiltration of anti-tumor immune cells at tumor sites. Therefore, UFA liposomes regulate GXP4 to exacerbate lipid peroxidation and provide a versatile liposome platform for enhancing anti-tumor therapy which could be readily extended to the delivery of anticancer agents.

The unsatisfactory therapeutic effect and long-term adverse effect markedly prevent inorganic nanomaterials from clinical transformation. In light of this, we developed a novel biodegradable theranostic agent (MnCO 3 :Ho 3+ @DOX/Ca 3 (PO 4 ) 2 @BSA, HMCDB) based on the sonosensitizer manganese carbonate (MnCO 3 ) coating with calcium phosphate (Ca 3 (PO 4 ) 2 ) and simultaneously loaded it with the chemotherapeutic drug doxorubicin (DOX). Due to the mild acidity of the tumor microenvironment (TME), the Ca 3 (PO 4 ) 2 shell degraded first, releasing substantial quantities of calcium ions (Ca 2+ ) and DOX. Meanwhile, with the ultrasound (US) irradiation, MnCO 3 produced enough reactive oxygen species (ROS) to cause oxidative stress in the cells, resulting in accumulation of Ca 2+ . Consequently, the cascade effect significantly amplified the therapeutic effect. Importantly, the nanocomposite can be completely degraded and cleared from the body, demonstrating that it was a promising theranostic agent for tumor therapy. Furthermore, the doped holmium ions (Ho 3+ ) and in situ generation of manganese ions (Mn 2+ ) in TME endow the nanoagent with the ability for tumor-specific bimodality T 1 /T 2 -weighted magnetic resonance imaging (MRI). This novel nanoplatform with low toxicity and biodegradability holds great potential for cancer diagnosis and treatment.

Chemical pollution has become a prominent environmental problem. In recent years, quantitative high-throughput screening (qHTS) assays have been developed for the fast assessment of chemicals' toxic effects. Toxicology in the 21st Century (Tox21) is a well-known and continuously developing qHTS project. Recent reports utilizing Tox21 data have mainly focused on setting up mathematical models for in vivo toxicity predictions, with less attention to intuitive qHTS data visualization. In this study, we attempted to reveal and summarize the toxic effects of environmental pollutants by analyzing and visualizing Tox21 qHTS data. Via PubMed text mining, toxicity/structure clustering, and manual classification, we detected a total of 158 chemicals of environmental concern (COECs) from the Tox21 library that we classified into 13 COEC groups based on structure and activity similarities. By visualizing these COEC groups' bioactivities, we demonstrated that COECs frequently displayed androgen and progesterone antagonistic effects, xenobiotic receptor agonistic roles, and mitochondrial toxicity. We also revealed many other potential targets of the 13 COEC groups, which were not well illustrated yet, and that current Tox21 assays may not correctly classify known teratogens. In conclusion, we provide a feasible method to intuitively understand qHTS data.

Temperature dynamics reflect the physiological state of cells, and accurate measurement of intracellular temperature helps to understand the biological processes. Herein, we report a novel nanothermometer by conjugating a fluorescent probe 3-ethyl-2-[4-(1,2,2-triphenylvinyl)styryl]benzothiazol-3-ium iodide (TPEBT) with a thermoresponsive polymer poly( N -isopropylacrylamide- co -tetrabutylphosphonium styrenesulfonate) [P(NIPAM- co -TPSS)]. The derived nanoprobe TPEBT-P(NIPAM- co -TPSS) self-assembles into micelles with TPEBT as hydrophobic core and PNIPAM as hydrophilic shell. It exhibits aggregation-induced emission (AIE) at λ ex /λ em = 420/640 nm in aqueous medium with a quantum yield of Φ F 11.9%. The rise in temperature transforms PNIPAM chains from linear to compact spheres to serve as the core of micelles, and meanwhile converts TPEBT from the state of aggregation to dispersion and redistributes in the micellar shell. Temperature-driven phase transition of P(NIPAM- co -TPSS) mediates the reversible aggregation and disaggregation of TPEBT and endows the nanothermometer with temperature-dependent AIE features and favorable sensitivity for temperature sensing in 32-40 °C. TPEBT-P(NIPAM- co -TPSS) is taken up by HeLa cells to distribute mainly in lysosomes. It enables quantitative visualization of in situ thermal dynamics in response to stimuli from carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, oligomycin, genipin, and lipopolysaccharide. The real-time monitoring of photothermal-induced intracellular temperature variation is further conducted.

Accurate diagnosis and highly effective treatment of glioblastoma are still challenges in clinic. Near-infrared (NIR) light triggered fluorescence imaging and photodynamic therapy (PDT) showed the potential for theranostics of glioblastoma, but the presence of blood-brain barrier (BBB) and hypoxia limited treatment effect. Herein, the novel theranostic nanoagents with YOF:Nd 3+ as core, MnO 2 as shell, and further loading photosensitizer (indocyanine green, ICG) and glucose oxidase (GOx) were successfully constructed, and further modified with lactoferrin to endow them with BBB penetration and target abilities (YOF:Nd 3+ @MnO 2 -ICG-GOx-LF, YMIGL). The YOF:Nd 3+ core with good fluorescence performances makes YMIGL act as promising probes for fluorescence imaging in the second biowindow (NIR-II FL). The combination of GOx and MnO 2 shell significantly increased the O 2 generation from the cascade reactions and consumed glucose, improving the treatment effect of PDT and achieving starvation treatment (ST). These theranostic nanoagents exhibit a highly efficient inhibition effect on orthotopic gliomas by cascade reactions, which improved PDT and ST.

Aberrant production of H 2 O 2 is involved in cancer. The levels of H 2 O 2 are significantly higher in tumor cells than in normal cells. It is important to develop fluorescent probes to image basal H 2 O 2 selectively in tumor cells. So far, a cancer cell-targeting probe to image basal H 2 O 2 has not been reported. Thus, we developed a fluorescent probe, BBHP , which contains benzil as a H 2 O 2 -recognition site and biotin as a target binding motif for the selective and sufficient detection of H 2 O 2 in tumor cells. BBHP enables a selective fluorescence turn-on response to H 2 O 2 . The binding of the probe with biotin receptors can greatly accelerate the fluorescence response to H 2 O 2 . As a result, BBHP can sufficiently image basal H 2 O 2 in biotin receptor-positive cancer cells and tumor tissues. Finally, BBHP was successfully applied to discriminate between cancerous and normal tissues.

In this work, an alternative flame-retardant filler based on phosphate- and urea-grafted bamboo charcoal (BC-m) at 10-30 wt % addition was aimed at improving the flame retardancy of polylactic acid (PLA) composites. The filler caused only a small reduction in strength properties but a slight increase in the modulus of elasticity of PLA composites. BC-m significantly improved the flame-retardant performance compared with pure BC. The limiting oxygen index (LOI) was 28.0 vol % when 10 wt % of BC-m was added, and 32.1 vol % for 30 wt % addition, which was much greater than the value of 22.5 vol % for 30 wt % pure BC. Unlike pure BC, adding BC-m at 20 wt % or more gave a UL-94 vertical flame test rating of V-0 with significantly reduced melt dripping. The peak heat release rate (pHRR) and total heat release (THR) of BC-m/PLA composites decreased by more than 50% compared with pure PLA, and the values for 20% BC-m were significantly less than that for 25% BC addition. The grafted biochar-based system provides an effective flame retardancy effect by a condensed-phase protective barrier through the rapid formation of a dense, honeycomb-like cross-linked carbonized char layer. The results suggest a promising route to enhancing the flame-retardant properties of biodegradable polymer composites using nontoxic, more environmentally friendly grafted biochar., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

The simultaneous control of the defect species and surface properties of semiconducting materials is a crucial aspect of improving photocatalytic performance, yet it remains challenging. Here, we synthesized Mg-Zr-codoped single-crystalline Ta 3 N 5 (Ta 3 N 5 :Mg+Zr) nanoparticles by a brief NH 3 nitridation process, exhibiting photocatalytic water reduction activity 45 times greater than that of pristine Ta 3 N 5 under visible light. A coherent picture of the relations between the defect species (comprising reduced Ta, nitrogen vacancies and oxygen impurities), surface properties (associated with dispersion of the Pt cocatalyst), charge carrier dynamics, and photocatalytic activities was drawn. The tuning of defects and simultaneous optimization of surface properties resulting from the codoping evidently resulted in the generation of high concentrations of long-lived electrons in this material as well as the efficient migration of these electrons to evenly distributed surface Pt sites. These effects greatly enhanced the photocatalytic activity. This work highlights the importance and feasibility of improving multiple properties of a catalytic material via a one-step strategy.

In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC 50 of 1.81 ± 0.04 μM and inhibit SARS-CoV-2 viral infection in cells with an EC 50 of 71.6 μM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.

There is an urgent need for reliable and effective models to study air pollution health effects on human lungs. Here, we report the utilization of human pluripotent stem cell (hPSC) induction models for human lung progenitor cells (hLPs) and alveolar type 2 epithelial cell-like cells (ATLs) for the toxicity assessment of benzo(a)pyrene, nano-carbon black, and nano-SiO 2 , as common air pollutants. We induced hPSCs to generate ATLs, which recapitulated key features of human lung type 2 alveolar epithelial cells, and tested the induction models for cellular uptake of nanoparticles and toxicity evaluations. Our findings reveal internalization of nano-carbon black, dose-dependent uptake of nano-SiO 2 , and interference with surfactant secretion in ATLs exposed to benzo(a)pyrene/nano-SiO 2 . Thus, hLP and ATL induction models could facilitate the evaluation of environmental pollutants potentially affecting the lungs. In conclusion, this is one of the first studies that managed to adopt hPSC pulmonary induction models in toxicology studies.

Thermochromic metal-organic frameworks (MOFs) are promising functional materials for a wide range of applications due to their ability to exhibit color variation under external temperature stimuli, yet the development of them with high cyclability and efficient regeneration processes remains challenging. Here, presented is a rare example of an ultrastable Ni(II)-MOF exhibiting an unprecedented reversible four-step color change between two complementary colors in a wide temperature range, which could be repeated for at least 500 cycles without losing crystallinity and thermochromic performance. Notably, the regeneration can be achieved within 1 min by simply letting the crystals cool naturally in the air, facilitated by the unique nature of the channels' inner surface. The reversible thermochromic behavior is owing to a series of reversible crystal structure changes with temperature, including the stepwise dehydration/rehydration process, and structural changes. This work facilitates the future development of more MOF-based reversible thermochromic materials with excellent performance and improved practical applicability.

The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)-methoxy poly(ethylene glycol), PLA-PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA-PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA-PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA-PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1- and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

The importance of arsenic metabolism by gut microbiota has been evidenced in risk characterization from As exposures. In this study, we evaluated the metabolic potency of human gut microbiota toward As(V)-sorbed goethite and jarosite, presenting different behaviors of As release, and the solid-liquid transformation and partitioning. The release of As occurred mainly in the small intestinal phase for jarosite and in the colon phase for goethite, respectively. We found higher degree of As(V) and Fe(III) reduction by human gut microbiota in the colon digests of goethite than jarosite. Speciation analysis using high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry and X-ray absorption near-edge spectroscopy, revealed that 43.2% and 8.5% of total As was present as As(III) in the liquid and solid phase, respectively, after goethite incubation, whereas almost all generated As(III) was in the colon digests of jarosite. Therefore, As bioaccessibility in human gastrointestinal tract was predominantly contributed to Fe(III) dissolution in jarosite, and to microbial reduction of Fe(III) and As(V) in goethite. It expanded our knowledge on the role of Fe minerals in human health risk assessment associated with soil As exposures.

The high levels of secondary metabolites in rapeseed play important roles in determining the oil quality and feeding value. Here, we characterized the metabolic profiles in seeds of various yellow- and black-seeded rapeseed accessions. Two hundred and forty-eight features were characterized, including 31 phenolic acids, 54 flavonoids, 24 glucosinolates, 65 lipid compounds, and 74 other polar compounds. The most abundant phenolic acids and various flavonoids (epicatechin, isorhamnetin, kaempferol, quercetin, and their derivatives) were widely detected and showed significant differences in distribution between the yellow- and black-seeded rapeseed. Furthermore, the related genes (e.g., BnTT3 , BnTT18 , BnTT10 , BnTT12 , and BnBAN ) involved in the proanthocyanidin pathway had lower expression levels in yellow-seeded rapeseed, strongly suggesting that the seed coat color could be mainly determined by the levels of epicatechin and their derivatives. These results improve our understanding of the primary constituents of rapeseed and lay the foundation for breeding novel varieties with a high nutritional value.

Either hypoxia in an acute ischemic stroke before thrombolysis or the oxygen-boost after thrombolysis cause a high level of free radicals, resulting in successive injuries to neurocytes. To treat an ischemic stroke, it is needed to scavenge free radicals, combining sequentially regulating hypoxia and oxygen-boost microenvironment. Here, we report an engineered nanosponge (Mn 3 O 4 @nanoerythrocyte-T7, MNET) that could remodel the microenvironment of a stroke by self-adapted oxygen regulating and free radical scavenging. With a long circulation time in blood due to the stealth effect of the erythrocyte and preferential accumulation in the infarct site by the assisting of T7 peptide, MNET exerts a distinct therapeutic effect in two stages of an ischemic stroke: (i) before thrombolysis, rescue neurocyte via rapid free radical scavenging and timely oxygen supply; (ii) after thrombolysis, suppress oxygen-boost via oxygen storage, as well as scavenge free radical to avoid reperfusion injury. MNET holds an attractive potential for ischemic stroke treatment via phased regulation of pathological microenvironment.

Due to the limitation of inorganic nanomaterials in present clinical applications induced by their inherent nonbiodegradability and latent long-term side effects, we successfully prepared double switch degradable and clearable trinickel monophosphide porous hollow nanospheres (NiP PHNPs) modified with bovine serum albumin (BSA). Attributed to their acidic and oxidative double switch degradation capacities, NiP PHNPs can be effectively excreted from mice without long-term toxicity. Moreover, because of the paramagnetic and high molar extinction coefficient property resulting from the strong absorption in the second near-infrared light (NIR II) biowindow, NiP PHNPs have potential to be used for photoacoustic imaging (PAI) and T 1 -weighted magnetic resonance imaging (MRI) guided photothermal ablation of tumors in the NIR II biowindow. Specifically, it is interesting that the hollow structure and acidic degradation property enable NiP PHNPs to act as intelligent drug carriers with an on-demand release ability. These findings highlight the great potential of NiP PHNPs in the cancer theranostics field and inspire us to further broaden the bioapplications of transition metal phosphides.

Despite rice consumption, rice bran as a byproduct of rice milling contains higher arsenic (As). The present study evaluated the metabolic potency of in vitro cultured human colon microbiota toward As from five rice bran products with 0.471-1.491 mg of As/kg. Arsenic bioaccessibility ranged from 52.8 to 78.8% in the gastric phase, and a 1.2-fold increase (66.0-95.8%) was observed upon the small intestinal phase. Subsequently, a significant decline of As bioaccessibility (11.3-63.6%) and a high methylation percentage of 18.5-79.8% were found in the colon phase. The predominant As species in the solid phase was always As(V) (49.6-63.4%), and As-thiolate complexes increased by 10% at the end of colon incubation. Human gut microbiota could induce As bioaccessibility lowering and As transformation in rice bran, which illustrated the importance of food-bound As metabolism in the human body. This will result in a better understanding of health implications associated with As exposures.

Tetrabromobisphenol A (TBBPA), as well as its alternatives Tetrabromobisphenol S (TBBPS) and Tetrachlorobisphenol A (TCBPA), are widely used halogenated flame retardants. Their high detection rates in human breast milk and umbilical cord serum have raised wide concerns about their adverse effects on human fetal development. In this study, we evaluated the cytotoxicity and neural developmental toxicity of TBBPA, TBBPS, and TCBPA with a mouse embryonic stem cell (mESC) system, at human body fluid and environmental relevant doses. All the three compounds showed similar trends in their cytotoxic effects. However, while TBBPA and TBBPS stimulated ESC neural differentiation, TCBPA significantly inhibited neurogenesis. Mechanistically, we demonstrated that, as far as the NOTCH (positive regulator) and WNT (negative regulator) pathways were concerned, TBBPA only partially and slightly disturbed them, whereas TBBPS significantly inhibited the WNT pathway, and TCBPA down-regulated the expression of NOTCH effectors but increased the WNT signaling, actions which both inhibited neural specification. In conclusion, our findings suggest that TBBPS and TCBPA may not be safe alternatives to TBBPA, and their toxicity need to be comprehensively evaluated.

Cadmium (Cd) in 8698 peanut samples collected from China in 2009-2014 was studied to evaluate its contamination level, distribution, and health risk. The average Cd concentration was 0.1684 mg kg -1 ; the range of 2.5-97.5% was 0.0191-0.4762 mg kg -1 , indicating the cadmium-contaminated peanut level was even lower. Some peanut strains for which protein contents had a significant correlation (Pearson correlation coefficient r = 0.86**) with the Cd concentration level should be of concern. Under the same soil Cd background, the difference in Cd contents in different peanut varieties is extremely significant. For example, the Cd concentration of Silihong is about 0.4522 mg kg -1 , being 7 times higher than that of Zhonghua 6. According to the exposure assessment using the probabilistic simulation method, the target hazard quotients (THQs) of all groups should be below 1. The THQ range in this study was from 0.0035 to 0.0202, suggesting that there were no potential noncinogenic effects in any group.

Persisters are a small fraction of drug-tolerant bacteria without any genotype variations. Their existence in many life-threatening infectious diseases presents a major challenge to antibiotic therapy. Persistence is highly related to toxin-antitoxin modules. HipA (high persistence A) was the first toxin found to contribute to Escherichia coli persistence. In this study, we used structure-based virtual screening for HipA inhibitors discovery and identified several novel inhibitors of HipA that remarkably reduced E. coli persistence. The most potent one decreased the persister fraction by more than five-fold with an in vitro K D of 270 ± 90 nM and an ex vivo EC50 of 46 ± 2 and 28 ± 1 μM for ampicillin and kanamycin screening, respectively. These findings demonstrated that inhibition of toxin can reduce bacterial persistence independent of the antibiotics used and provided a framework for persistence treatment by interfering with the toxin-antitoxin modules.

Black phosphorus (BP) is one of the most attractive graphene analogues, and its properties make it a promising nanomaterial for chemical sensing. However, mono- and few-layer BP flakes are reported to chemically degrade rapidly upon exposure to ambient conditions. Therefore, little is known about the performance and sensing mechanism of intrinsic BP, and chemical sensing of intrinsic BP with acceptable air stability remains only theoretically explored. Here, we experimentally demonstrated the first air-stable high-performance BP sensor using ionophore coating. Ionophore-encapsulated BP demonstrated significantly improved air stability. Its performance and sensing mechanism for trace ion detection were systematically investigated. The BP sensors were able to realize multiplex ion detection with superb selectivity, and sensitive to Pb(2+) down to 1 ppb. Additionally, the time constant for ion adsorption extracted was only 5 s. The detection limit and response rate of BP were both superior to those of graphene based sensors. Moreover, heavy metal ions can be effectively detected over a wide range of concentration with BP conductance change following the Langmuir isotherm for molecules adsorption on surface. The simplicity of this ionophore-encapsulate approach provides a route for achieving air-stable intrinsic black phosphorus sensors that may stimulate further fundamental research and potential applications.

Arsenic (As) speciation and distribution are two important factors in assessing human health risk from As-contaminated soil. In this study, we used the combination of physiologically based extraction test (PBET) and Simulator of Human Intestinal Microbial Ecosystem (SHIME) to determine soil As metabolism by human gut microbiota. The results showed that the percentage of soil arsenate [As(V)] transformation reached 22.1-38.2%, while that of arsenite [As(III)] attained 66.5-92.0%; 30.1-56.4% of As(V) transformed was attached to the soil solid phase. In comparison to sequential extraction results, almost all amorphous Fe/Al-oxide-bound As was liberated in the colon phase. An X-ray absorption near-edge structure (XANES) showed that the As(III) percentage in the soil solid phase reached 16.6-26.9% and reached 73.4% (soil 1) in the colon phase. Additionally, plenty of As(III) and different extents of methylation were also observed in colon extraction solution. As bioaccessibility in the colon phase was 1.8-2.8 times that in the small intestinal phase. Our results indicated that human gut microbiota increased As bioaccessibility, and large amounts of As(III) were adsorbed onto the soil solid phase as a result of microbial reduction. Determining As speciation and distribution in extraction solution and soil solid phases will allow for an accurate assessment of the risk to human health upon soil As exposure.

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 μg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

In this Perspective, we focus on new, systems-centric views of structure-based drug design (SBDD) that we believe will impact future drug discovery research and development. We will first discuss new ways to identify drug targets based on systems intervention analysis, and then we will introduce emerging SBDD methods driven by advancements in systems biology.

Graphene and graphene-based nanomaterials display novel and beneficial chemical, electrical, mechanical, and optical characteristics, which endow these nanomaterials with promising applications in a wide spectrum of areas such as electronics and biomedicine. However, its toxicity on health remains unknown and is of great concern. In the present study, we demonstrated that graphene oxide (GO) induced necrotic cell death to macrophages. This toxicity is mediated by activation of toll-like receptor 4 (TLR4) signaling and subsequently in part via autocrine TNF-α production. Inhibition of TLR4 signaling with a selective inhibitor prevented cell death nearly completely. Furthermore, TLR4-deficient bone marrow-derived macrophages were resistant to GO-triggered necrosis. Similarly, GO did not induce necrosis of HEK293T/TLR4-null cells. Macrophagic cell death upon GO treatment was partially attributed to RIP1-RIP3 complex-mediated programmed necrosis downstream of TNF-α induction. Additionally, upon uptake into macrophages, GO accumulated primarily in cytoplasm causing dramatic morphologic alterations and a significant reduction of the macrophagic ability in phagocytosis. However, macrophagic uptake of GO may not be required for induction of necrosis. GO exposure also caused a large increase of intracellular reactive oxygen species (ROS), which contributed to the cause of cell death. The combined data reveal that interaction of GO with TLR4 is the predominant molecular mechanism underlying GO-induced macrophagic necrosis; also, cytoskeletal damage and oxidative stress contribute to decreased viability and function of macrophages upon GO treatment.

Natural killer T cells (NKT cells) respond to presentation of specific glycolipids with release of a variety of proinflammatory and immunomodulatory cytokines. The repertoire of glycolipid antigens for these cells includes alpha-glycosylceramides, alpha-glycosyldiacylglycerols, and the triglycosylceramide iGb3. Two features of iGb3 set it apart from these other antigens: (i) three sugars are required for stimulation and (ii) the glycosidic bond between ceramide and the proximal sugar is beta in iGb3, whereas it is alpha in other antigens. We have synthesized the alpha versions of iGb3 and Gb3 and demonstrate that they are effective antigens for NKT cells and that they do not require lysosomal processing to the monoglycosylceramides for stimulation. These triglycosylceramides constitute a new class of antigen that stimulates NKT cells comparably to monoglycosylceramides.

A key factor in the potential clinical utility of membrane-active antibiotics is their cell selectivity (i.e., prokaryote over eukaryote). Cationic steroid antibiotics were developed to mimic the lipid A binding character of polymyxin B and are shown to bind lipid A derivatives with affinity greater than that of polymyxin B. The outer membranes of Gram-negative bacteria are comprised primarily of lipid A, and a fluorophore-appended cationic steroid antibiotic displays very high selectivity for Gram-negative bacterial membranes over Gram-positive bacteria and eukaryotic cell membranes. This cell selectivity of cationic steroid antibiotics may be due, in part, to the affinity of these compounds for lipid A., (Copyright 2004 American Chemical Society)

Glycolipid presentation by CD1 proteins has emerged as an important aspect of antigen recognition, and presentation of alpha-glycosylceramides by CD1d to natural killer T cells has become a central focus in understanding how glycolipid presentation can influence immune responses. An alpha-galactosylceramide containing relatively long lipid chains has been the subject of intense study because, when presented by CD1d to natural killer T cells, it stimulates the release of both proinflammatory and immunomodulatory cytokines. Using an efficient synthesis of alpha-galactosylceramides, we have prepared a series of glycolipids in which the lipid chain lengths have been incrementally varied. The responses of natural killer T cells to these glycolipids have been determined, and we have found that truncation of the phytosphingosine lipid chain increases the relative amounts of immunomodulatory cytokines released. In similar fashion, the length of the acyl chain in alpha-galactosylceramides influences cytokine release profiles.

Lipid A is the causative agent of Gram-negative sepsis, a leading cause of mortality among hospitalized patients. Compounds that bind lipid A can limit its detrimental effects. Polymyxin B, a cationic peptide antibiotic, is one of the simplest molecules capable of selectively binding lipid A and may serve as a model for further development of lipid A binding agents. However, association of polymyxin B with lipid A is not fully understood, primarily due to the low solubility of lipid A in water and inhomogeneity of lipid A preparations. To better understand lipid A-polymyxin B interaction, pure lipid A derivatives were prepared with incrementally varied lipid chain lengths. These compounds proved to be more soluble in water than lipid A, with higher aggregation concentrations. Isothermal titration calorimetric studies of these lipid A derivatives with polymyxin B and polymyxin B nonapeptide indicate that binding stoichiometries (peptide to lipid A derivative) are less than 1 and that affinities of these binding partners correlate with the aggregation states of the lipid A derivatives. These studies also suggest that cooperative ionic interactions dominate association of polymyxin B and polymyxin B nonapeptide with lipid A.